Atorvastatin

FDA Approves Broader Range of Initial Doses - April 29, 2002

Pfizer Inc has announced that the Food and Drug Administration (FDA) has approved a change in the product labeling for Lipitor® (atorvastatin), which allows for great flexibility in determining the initial starting dose. The new labeling for this lipid-lowering drug noted typical initial doses are 10-20 mg once daily, but doses as high as 40 mg once daily are acceptable in patients requiring a large reduction in LDL-C (>45%) to reach goal levels.

Pronunciation (a TORE va sta tin)

• Antacid Drug Interactions
• Lipid-Lowering Agents

U.S. Brand Names Lipitor®

Generic Available No

Canadian Brand Names Lipitor®

Pharmacologic Category Antilipemic Agent, HMG-CoA Reductase Inhibitor

Use Adjunct to diet for the reduction of elevated total and LDL cholesterol, apolipoprotein B, and triglyceride levels in patients with hypercholesterolemia (types IIa, IIb, and IIc); adjunctive therapy to diet for treatment of elevated serum triglyceride levels (type IV); treatment of primary dysbetalipoproteinemia (type III) in patients who do not respond adequately to diet; to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb). Also may be used in hypercholesterolemic patients without clinically evident heart disease to reduce the risk of myocardial infarction, to reduce the risk for revascularization, and reduce the risk of death due to cardiovascular causes

Pregnancy Risk Factor X

Lactation Enters breast milk/contraindicated

Contraindications Hypersensitivity to atorvastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy

Warnings/Precautions Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is dose-related and is increased with concurrent use of lipid-lowering agents which may cause rhabdomyolysis (gemfibrozil, fibric acid derivatives, or niacin at doses 1 g/day) or during concurrent use with potent CYP3A3/4 inhibitors (including amiodarone, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, nefazodone, grapefruit juice in large quantities, verapamil, or protease inhibitors such as indinavir, nelfinavir, or ritonavir). Weigh the risk versus benefit when combining any of these drugs with atorvastatin. Discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis.

>10%: Central nervous system: Headache (3% to 17%)

2% to 10%:

<2% (Limited to important or life-threatening): Pneumonia, dyspnea, epistaxis, face edema, fever, photosensitivity, malaise, edema, gastroenteritis, elevated transaminases, colitis, vomiting, gastritis, xerostomia, rectal hemorrhage, esophagitis, eructation, glossitis, stomatitis, anorexia, increased appetite, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gingival hemorrhage, tenesmus, hepatitis, pancreatitis, cholestatic jaundice, paresthesia, somnolence, abnormal dreams, decreased libido, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia, leg cramps, bursitis, myasthenia, myositis, tendinous contracture, pruritus, alopecia, dry skin, urticaria, acne, eczema, seborrhea, skin ulcer, cystitis, hematuria, impotence, dysuria, nocturia, epididymitis, fibrocystic breast disease, vaginal hemorrhage, nephritis, abnormal urination, amblyopia, tinnitus, deafness, glaucoma, taste loss, taste perversion, palpitation, vasodilation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina, hypertension, hyperglycemia, gout, weight gain, hypoglycemia, ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechiae, pharyngitis, rhinitis, myopathy

Postmarketing reports: Anaphylaxis, angioneurotic edema, bullous rashes, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, rhabdomyolysis

Additional class-related events or case reports (not necessarily reported with atorvastatin therapy): Myopathy, increased CPK (>10x normal), rhabdomyolysis, renal failure (secondary to rhabdomyolysis), alteration in taste, impaired extraocular muscle movement, facial paresis, tremor, memory loss, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, depression, psychic disturbance, hypersensitivity reaction, angioedema, anaphylaxis, systemic lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, increased ESR, eosinophilia, arthritis, urticaria, photosensitivity, fever, chills, flushing, malaise, dyspnea, rash, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, pancreatitis, hepatitis, cholestatic jaundice, fatty liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, alopecia, nodules, skin discoloration, dryness of skin/mucous membranes, nail changes, gynecomastia, decreased libido, erectile dysfunction, impotence, cataracts, ophthalmoplegia, elevated transaminases, increased alkaline phosphatase, increased GGT, hyperbilirubinemia, thyroid dysfunction

Overdosage/Toxicology Few symptoms are anticipated. Treatment is supportive.

Drug Interactions CYP3A3/4 enzyme substrate

Antacids: Plasma concentrations may be decreased when given with magnesium-aluminum hydroxide containing antacids (reported with atorvastatin and pravastatin). Clinical efficacy is not altered, no dosage adjustment is necessary

Cholestyramine reduces absorption of several HMG-CoA reductase inhibitors; separate administration times by at least 4 hours.

Cholestyramine and colestipol (bile acid sequestrants): Cholesterol-lowering effects are additive.

Clofibrate and fenofibrate may increase the risk of myopathy and rhabdomyolysis.

CYP3A3/4 inhibitors (amiodarone, clarithromycin, cyclosporine, danazol, diltiazem, fluvoxamine, erythromycin, fluconazole, itraconazole, ketoconazole, miconazole, nefazodone, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, troleandomycin, and verapamil) increase atorvastatin blood levels; may increase the risk of atorvastatin-induced myopathy and rhabdomyolysis. The risk of myopathy and rhabdomyolysis due to concurrent use of a CYP3A3/4 inhibitor with atorvastatin is probably less than lovastatin or simvastatin.

Grapefruit juice: May inhibit metabolism of atorvastatin via CYP3A3/4; more likely to occur with lovastatin or simvastatin; avoid high dietary intake of grapefruit juice

Niacin may increase the risk of myopathy and rhabdomyolysis.

Food: Atorvastatin serum concentrations may be increased by grapefruit juice; avoid concurrent intake of large quantities (>1 quart/day).

Herb/Nutraceutical: St John's wort may decrease atorvastatin levels.

Mechanism of Action Inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism

Onset of action: Initial changes: 3-5 days; Maximal reduction in plasma cholesterol and triglycerides: 2 weeks

Absorption: Rapid

Protein binding: 98%

Metabolism: To active ortho- and parahydroxylated derivates and an inactive beta-oxidation product; undergoes enterohepatic recirculation

Half-life elimination: Parent drug: 14 hours

Time to peak, serum: 1-2 hours

Excretion: Urine (2% as unchanged drug)

Dosage Adults: Oral: Initial: 10-20 mg once daily; patients requiring >45% reduction in LDL-C may be started at 40 mg once daily; titrate initial dose to achieve goal (maximum dose: 80 mg once daily)

Dosing adjustment in renal impairment: No dosage adjustment is necessary.

Dosing adjustment in hepatic impairment: Do not use in active liver disease.

Administration May take with food if desired; may take without regard to time of day.

Monitoring Parameters Lipid levels after 2-4 weeks; LFTs, CPK

It is recommended that liver function tests (LFTs) be performed prior to and at 12 weeks following both the initiation of therapy and any elevation in dose, and periodically (eg, semiannually) thereafter

Dietary Considerations May take with food if desired; may take without regard to time of day. Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 3-6 months and the diet should be continued during drug therapy.

Patient Information May take with meals at any time of day. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You will need laboratory evaluation during therapy. May cause headache (mild analgesic may help); diarrhea (yogurt or buttermilk may help); euphoria, giddiness, confusion (use caution when driving or engaging in tasks that require alertness until response to medication is known). Report unresolved diarrhea, excessive or acute muscle cramping or weakness, changes in mood or memory, yellowing of skin or eyes, easy bruising or bleeding, and unusual fatigue. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during therapy. Consult prescriber for instructions on appropriate contraceptive measures. This drug can cause severe fetal defects. Do not donate blood for same period of time. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations Statin therapy should be held temporarily in patients with conditions (ie, sepsis; hypotension; major surgery; trauma; severe metabolic; endocrine or electrolyte disorders; uncontrolled seizures) that predispose them to acute renal failure secondary to rhabdomyolysis.

Clinical trials have shown that atorvastatin can lower LDL-C up to 60% and TG up to 40%. This may allow atorvastatin to be used as monotherapy in some patients requiring combination therapy to adequately lower LDL-C and TG. However, further studies are required to evaluate and compare atorvastatin with combination therapy. Atorvastatin has a safety profile similar to other drugs in its class.

HMG-CoA reductase inhibitors are effective in secondary prevention of cardiovascular events in patients with hyperlipidemia. In these situations, the target of therapy is a reduction in LDL cholesterol to <100 mg/dL. HMG-CoA reductase inhibitors have also been shown to be effective in primary prevention of coronary artery disease in individuals without established cardiovascular disease but who have multiple risk factors. Among the HMG-CoA reductase inhibitors, atorvastatin produces the greatest reduction in LDL cholesterol at therapeutic doses. Important side effects relate to elevated liver enzymes and rhabdomyolysis. LFTs need to be monitored at specified intervals.

Cardiovascular Considerations HMG-CoA reductase inhibitors are effective in secondary prevention of cardiovascular events in patients with hyperlipidemia. In these situations, the target of therapy is a reduction in LDL cholesterol to <100 mg/dL. HMG-CoA reductase inhibitors have also been shown to be effective in primary prevention of coronary artery disease in individuals without established cardiovascular disease but who have multiple risk factors. Selection of lipid-lowering therapy should be based on the patient's lipid profile, concomitant disease states, and the cost of therapy. The benefits of lipid-lowering are also compelling in women and in the elderly. Many patients with coronary artery disease and hyperlipidemia may unfortunately remain untreated, despite the compelling beneficial effects of lipid-lowering therapy on cardiovascular morbidity and mortality. Among the HMG-CoA reductase inhibitors, atorvastatin produces the greatest reduction in LDL cholesterol at therapeutic doses. Important side effects relate to elevated liver enzymes and rhabdomyolysis. LFTs need to be monitored at specified intervals.

Important drug-drug interactions included gemfibrozil, niacin, erythromycin, cyclosporine, anticoagulants, itraconazole, and ketoconazole.

Dental Health: Effects on Dental Treatment No effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions No information available to require special precautions

Mental Health: Effects on Mental Status Rare reports of euphoria

Mental Health: Effects on Psychiatric Treatment None reported

Dosage Forms Tablet: 10 mg, 20 mg, 40 mg, 80 mg

Fonarow GC, French WJ, Parsons LS, et al, "Use of Lipid-Lowering Medications at Discharge in Patients With Acute Myocardial Infarction: Data From the National Registry of Myocardial Infarction 3,"Circulation, 2001, 103(1):38-44.

Koren MJ, Smith DG, Hunninghake DB, et al, "The Cost of Reaching National Cholesterol Education Program (NCEP) Goals in Hypercholesterolaemic Patients. A Comparison of Atorvastatin, Simvastatin, Lovastatin and Fluvastatin,"Pharmacoeconomics, 1998, 14(1):59-70.

Phillips BG, Yim JM, Brown EJ Jr, et al, "Pharmacologic Profile of Survivors of Acute Myocardial Infarction at United States Academic Hospitals,"Am Heart J, 1996, 131(5):872-8.

Pitt B, Waters D, Brown WV, et al, "Aggressive Lipid-Lowering Therapy Compared With Angioplasty in Stable Coronary Artery Disease. Atorvastatin Versus Revascularization Treatment Investigators,"N Engl J Med, 1999, 341(2):70-6.

"Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II),"JAMA, 1993, 269(23):3015-23.

International Brand Names Ampliar® (AR); Ateroclar® (AR); Cardyl® (ES); Lipitor (AU, BE, CA, GB, ID, IE, IT, MX, NL, NZ, NO, ZA, SE, TR); Prevencor (ES); Sortis® (AT, DE, CH); Tahor (FR); Torvast® (IT); Totalip (IT); Xarator® (IT); Zarator (DK, PT, ES)